| Cone snails are carnivorous marine gastropods that hunt marine worms, marine mollusks and fish. Their venoms are complex mixtures of toxins which include highly disulphide bonded peptides (conotoxins). Conotoxins target ion channels and receptors in the nervous systems of organisms that the snails interact with (i.e., their prey, their competitors and their predators).; Conotoxins are often highly specific for particular subtypes within a given family of receptor or ion channel. As a result, certain conotoxins have become valuable neurological tools and potentially important therapeutic agents. The goal of the work described in this thesis was the identification of novel conotoxins with unique and possibly useful properties. The work focused on α and αA-conotoxins, which are antagonists of nicotinic acetylcholine receptors (nAChRs).; Chapter II describes the isolation and characterization of the novel conotoxin αA-EIVA. It inhibits the muscle subtype nAChRs at low nanomolar concentrations, and in this regard, it is very similar to previously characterized α-conotoxins. However, uniquely, αA-EIVA blocks at both the α/δ and α/γ subunit interfaces of the muscle nAChR with equally high affinities. It is thus a novel probe for both the α/δ and α/γ binding sites of the muscle nAChR.; Chapter III describes the characterization of a novel α-conotoxin, α-CTx ImII, from Conus Imperialis. α-CTx ImII inhibits the α7nAChR subtype with a mid-micromolar affinity but, very surprisingly, it does not compete with α-bungarotoxin, a classical competitive inhibitor of this receptor. α-CTx ImII thus represents a novel probe for a distinct antagonist site. Chapter IV describes preliminary work done to elucidate the novel α-CTx ImII binding site.; Chapter V describes a study that investigated the possibility of generating synthetic α-conotoxins with desirable properties by combinatorial modification of the intercystine residues of natural α-conotoxins. The natural a conotoxin α-CTx ImI was successfully modified to give a new peptide with a much slower off rate from the α7 subtype nAChR. |
